Structure-based design,synthesis and in vitro antiproliferative effects studies of novel dual BRD4/HDAC inhibitors |
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| Authors: | Mingfeng Shao Linhong He Li Zheng Lingxiao Huang Yuanyuan Zhou Taijing Wang Yong Chen Mingsheng Shen Fang Wang Zhuang Yang Lijuan Chen |
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| Affiliation: | 1. Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan 610041, PR China;2. Sichuan Provincial Key Laboratory for Organ Transplantation Translation Medicine, Hospital of the University of Electronic Science and Technology of China and Sichuan Provincial People’s Hospital, Chengdu, Sichuan 610072, PR China |
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| Abstract: | Histone acetylation marks play important roles in controlling gene expressions and are removed by histone deacetylases (HDACs). These marks are read by bromodomain and extra-terminal (BET) proteins, whose targeted inhibitors are under clinical investigation. BET and HDAC inhibitors have been demonstrated to be synergistically killing in Mycinduced murine lymphoma. Herein, we combine the inhibitory activities of BET and HDAC into one molecule through structure-based design method and evaluate its function. The majority of these synthesized compounds showed inhibitory activity against second bromdomains(BRD) of BRD4 and HDAC1. Among them, 16ae presented anti-proliferative effects against human acute myelogenous leukemia (AML) cell lines in vitro, and 16ae is confirmed to reduce the expression of Myc by Western blot analysis. Those results indicated that 16ae is a potent dual BRD4/HDAC inhibitor and deserves further investigation. |
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| Keywords: | BET HDAC Dual inhibitors Myc AML |
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